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Cerebral vascular calcium signaling in diabetic Alzheimer's disease-related dementias

糖尿病阿尔茨海默病相关痴呆的脑血管钙信号传导

基本信息

批准号：
10117843
负责人：
YONG-XIAO WANG
金额：
$ 32.6万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-15 至 2024-08-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10117843
关键词：
Address Agreement Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Animals Award Biology Blood Blood Vessels Blood flow Calcium Signaling Cell Hypoxia Cells Cerebrovascular Circulation Cerebrum Cessation of life Cognitive Complex Data Dementia Deterioration Development Diabetes Mellitus Diabetic mouse Disease Dissociation Funding Funding Opportunities Hypoxia Impaired cognition In Vitro Knock-out Lead Link Mediating Mediation Memory Memory Loss Memory impairment Mitochondria Molecular Mus Nerve Degeneration Organ Oxidative Stress Pathologic Pathway interactions Pilot Projects Process Production Reactive Oxygen Species Research Research Personnel Rieske iron-sulfur protein Risk Factors Role Ryanodine Receptor Calcium Release Channel Series Site Smooth Muscle Smooth Muscle Myocytes Tacrolimus Binding Proteins Testing United States National Institutes of Health Vascular Dementia Vascular Smooth Muscle Wild Type Mouse Work antioxidant therapy base cerebral artery cerebral hypoperfusion cerebrovascular comorbidity diabetic experimental study glucose metabolism improved in vivo innovation knockout gene new therapeutic target novel overexpression programs protein expression response therapeutic target therapeutically effective vascular cognitive impairment and dementia vasoconstriction

项目摘要

Alzheimer's disease (AD) and AD-related dementias (ADRD) are the common incurable neurodegenerative even conditions characterized by progressive cognitive deterioration, memory decline and death. The major forms of ADRD include vascular contributions to cognitive impairment and dementia (VCID). In agreement, vascular dementia is the second most common form of dementia and the most frequent comorbidity with AD. Diabetes may production is a leading factor in the development of VCID; the ole of diabetes primarily occur due to the abnormal glucose metabolism and i ncreased reactive oxygen species (ROS) in cerebral vascular smooth muscle cells (CASMCs) r . In support, antioxidant therapies have shown promising results in protecting against diabetes-induced VCID and other dementias. the molecular mechanisms that link diabetes to the development of VCID remain to be elucidated, and current treatments for these diseases are neither always effective nor specific. The Based on our preliminary findings with previous work, in this project, we propose a novel central hypothesis that diabetes increases Rieske iron-sulfur protein (RISP)-mediated mitochondrial ROS, dissociates FK506 binding protein 12.6 (FKBP12.6) from type-2 ryanodine receptor (RyR2) to remove its inhibitory effect on RyR2 channel and induce Ca2+ release, which causes cerebral vasoconstriction and cerebral blood flow reduction, thereby leading to progressive memory loss, cognitive decline and VCID. To test this exciting hypothesis, we will conduct a series of mechanistic studies primarily by employing smooth muscle-specific RISP, RyR2, and FKBP12.6 knockout (KO) and/or overexpression (OE) mice with other complementary advanced experimental approaches to address the following specific questions (Specific Aims): Aim 1: Are the increased RISP-mediated mitochondrial ROS in CASMCs essential for VCID induced by diabetes? Aim 2: Is RyR2/FKBP12.6 complex dissociation a key consequence for the increased RISP-mediated mitochondrial ROS to mediate VCID induced by diabetes? The objectives of the present proposal are not only to enhance our understanding of the molecular mechanisms for VCID, ADRD devastating diseases. and AD, but also help to identify novel therapeutic targets for these common

阿尔茨海默病 (AD) 和 AD 相关痴呆症 (ADRD) 是常见的无法治愈的疾病神经退行性疾病甚至以进行性认知衰退、记忆力下降为特征的疾病死亡。 ADRD 的主要形式包括血管导致的认知障碍和痴呆（VCID）。一致认为，血管性痴呆是第二常见的痴呆形式，也是最常见的痴呆形式。 AD 常见的合并症。糖尿病可能生产是VCID发展的主导因素；糖尿病的OL 主要是由于葡萄糖代谢异常和活性氧（ROS）增加所致脑血管平滑肌细胞 (CASMC) r 。作为支持，抗氧化疗法已经在预防糖尿病引起的 VCID 和其他痴呆症方面显示出有希望的结果。这将糖尿病与 VCID 发展联系起来的分子机制仍有待阐明，目前对这些疾病的治疗既不总是有效也不具体。这根据我们之前工作的初步发现，在这个项目中，我们提出了一种新颖的中心糖尿病增加 Rieske 铁硫蛋白 (RISP) 介导的线粒体 ROS 的假设，将 FK506 结合蛋白 12.6 (FKBP12.6) 从 2 型兰尼碱受体 (RyR2) 上解离，以去除其抑制RyR2通道并诱导Ca2+释放，引起脑血管收缩，脑血流量减少，从而导致进行性记忆丧失、认知能力下降和VCID。为了测试这个令人兴奋的假设，我们将主要通过采用平滑肌特异性 RISP、RyR2 和 FKBP12.6 敲除 (KO) 和/或过表达 (OE) 小鼠其他补充的高级实验方法来解决以下具体问题（具体目标）：目标 1：CASMC 中 RISP 介导的线粒体 ROS 增加对于 VCID 诱导是否至关重要糖尿病？目标 2：RyR2/FKBP12.6 复合体解离是 RISP 介导的增加的关键结果吗？线粒体ROS介导糖尿病引起的VCID？本提案的目的不仅是增强我们对分子生物学的理解 VCID、ADRD 机制毁灭性的疾病。和广告，还有助于确定这些常见的新治疗靶点